1-oxime substituted quinolizines



United States Patent 3,518,269 l-OXIME SUBSTITUTED QUINOLIZINES RichardE. Brown, Hanover, and Robert I. Meltzer, Rockaway, N.J., assignors toWarner-Lambert Pharmaceutical Company, Morris Plains, N.J., acorporation of Delaware No Drawing. Filed May 4, 1967, Ser. No. 636,024

Int. Cl. C07d 101/00 US. Cl. 260-286 3 Claims ABSTRACT OF THE DISCLOSUREThe present invention relates to l-oxime substituted quinolizines of theFormula I:

(I) wherein R and R represent hydrogen, hydroxy, or lower alkoxy; Rrepresents hydrogen, or lower alkyl; It may be 1, 2, or 3.

The present invention relates to novel l-oxime substituted quinolizinesof formula:

wherein R and R represent hydrogen, hydroxy, or lower alkoxy of 1 to 6carbon atoms, such as methoxy, ethoxy, propoxy, and the like; Rrepresents hydrogen or lower alkyl, such as methyl, ethyl, propyl, andthe like; It may be 1, 2, or 3.

The compounds of this invention increase the strength of skeletalmuscles in a mammalian host and are therefore, useful as agents toincrease the strength of skeletal muscle. They are used in conditionsassociated with the loss of skeletal muscle strength. In order to usethese compounds, they are combined with an inert pharmaceutical carrier,such as lactose, starch, mannitol, dicalcium phosphates, and the like,to form dosage forms, such as tablets, powders, suspensions, and thelike. They are administered orally or by parenteral injection at a doseof about 100 to 500 mg. several times daily.

The compounds of this invention are useful as intermediates for theproduction of compounds of the formula:

NHz Ra (III) ice Compound III may be obtained by reducing compound Iwith a suitable reducing agent, as for example, lithium aluminumhydride. The resulting compound III is useful in the treatment ofcirculatory collapse and may be used in accordance with the teachings ofThe Journal of Pharmacology and Experimental Therapeutics, vol. 147, No.2, p. 225, et. seq.

EXAMPLE 1 The starting compound II may be prepared according to theteachings disclosed in our co-pending application, Ser. No. 248,872,filed Jan. 3, 1963 now US. Pat. No. 3,341,543, or that disclosed inTetrahedron Letters 1581 (1963).

The compounds of this invention form acid addition salts withpharmaceutically acceptable acids such as hydrochloric acid, hydrobromicacid, hydriodic acid, nitric acid, phosphoric acid, sulfuric acid;acetic acid, citric acid, tartaric acid, lactic acid, benzenesulfonicacid, toluene sulfonic acid, etc., and these salts are also within thescope of this invention.

The following examples are included in order further to illustrate theinvention.

23,4,4a,6,7,1 lb,l2, l 3,13a-decahydro-9, l O-dimethoxy-13a-methy1-1H-dibenzo [a,f] quinolizine-l-one-oximehydrochloride Asolution of 12.5 g. of 2,3,4,4a6,7,11b,12,l3,13a-decahydro 9, 10dimethoxy 13a methyl-1H dibenzo [a,f] quinolizine-l-onc in ml. each ofethanol and pyridine is treated with 6 grams of hydroxylaminehydrochloride in 25 ml. of ethanol. The solution is stirred at refluxfor 4 hrs. during which time precipitation of a white solid takes place.The slurry is cooled and filtered, and the product is air dried to give2,3,4,4a,6,7,1 1b,12,l3a-decahydro 9,10 dimethoxy 13a -methyl 1H dibenzo[a,f] quinolizine-1-one-oxime-hydrochloride as white crystals, M.P.247250. The melting point may be raised to 250252 by recrystallizationfrom water. The free base is obtained by treating the hydrochloride with5% sodium hydroxide as described in Example 2.

The compounds of this invention may be prepared by reacting a ketone ofthe formula:

with a reagent such as hydroxylamine or its acid addition salts, such asits hydrochloride or its sulfate salt. Such reactions are preferablycarried out in an inert solvent, such as a lower molecular weightalcohol in the presence of a base, such as an alkali metal hydroxide,for example, sodium or potassium hydroxide. Such reactions may also becarried out in an organic base, such as pyridine and the like.

EXAMPLE 2 iii/ CHzO

1,2,3,3a,5,6,10b,1 1,12, l2a-decahydro-8-methoxy-12aethyl-benz [a]cyclopenta [f] quinolizinel-one-oxime In the same way as described inExample 1, 10 g. of 1,2,3,3a,5,6,10b,11,12,12a-decahydro 8methoxy-lZaethy1-benz[a]cyc1openta[f]quinolizine-1-one gives thehydrochloride of 1,2,3,3a,5,6,lb,11,12,12a-decahydro-8- methoxy 12aethyl-benz[a]cyclopenta[f]quinolizinel-one-oxime. This is dissolved in100 ml. of water, made basic with sodium hydroxide, and the basefiltered and recrystallized from ethanol to give 1,2,3,3a,5,6,10b,11,12,12a-decahydro-8-methoxy-12a-ethylbenz[a]cyclopenta[f]quinolizine-l-one-oxime as white crystals, M.P.208-210".

We claim:

1. A member selected from the group consisting of 4 a free base of theformula:

N-OH Ra II (oHz)u References Cited UNITED STATES PATENTS 3,150,1359/1964 Forman 260-283 X 3,326,920 6/1967 Stanaback et al. 2602863,326,921 6/1967 Stanaback et a1 260---286 3,341,543 9/1967 Melzer et a1260287 X DONALD G. DAUS, Primary Examiner U.S. Cl. X.R. 424-25 8

